T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and transplantation, and is most likely operative during clinical organ transplantation in humans. Anergy involves the functional inactivation of inappropriate T cell responses, and is thought to be the result of active silencing of effector genes such as interleukin-2 (IL-2). Our progress during the first funding period of this grant established that cell cycle progression is necessary for activated T cells to escape anergy during a productive immune response, and defined a previously unappreciated role for cyclin-dependent kinases (CDK) and their genetically-encoded inhibitory proteins in the decision between T cell immunity and tolerance. The activity of these kinases opposed the induction of T cell clonal anergy in vitro, and genetic dysregulation of CDK activity during organ transplantation interfered with tolerance induced by costimulatory blockade. PUBLIC HEALTH RELEVANCE The goal of this proposal is to explore the molecular mechanisms by which cyclin-dependent kinases regulate T lymphocyte function, and to evaluate the potential of these molecules as therapeutic targets in pre-clinical models of organ transplantation. A deeper understanding of the molecular events underlying T cell tolerance could lead to new approaches to induce tolerance in the setting of autoimmunity and transplantation, and therefore the research proposed in the is application is consistent with and highly relevant to the NIH/HHS goal of improving human health.